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A R Campos-Contreras, A P Juárez-Mercado, A González-Gallardo, R Chávez-Genaro, E Garay, D L De Ita-Pérez, M Díaz-Muñoz, F G Vázquez-Cuevas
Extracellular purines through specific receptors have been recognized as new regulators of ovarian function. It is known that P2Y2 receptor activity induces theca cell proliferation, we hypothesized that purinergic signaling controls the changes related with hyperthecosis in polycystic ovarian syndrome (PCOS). The aim of this study was to analyze the expression of UTP-sensitive P2Y receptors and their role in theca cells (TC) proliferation in experimentally-induced PCOS (EI-PCOS). In primary cultures of TC from intact rats, all the transcripts of P2Y receptors were detected by PCR; in these cells UTP (10 μM) induced extracellular signal-regulated kinases (ERK) phosphorylation...
January 9, 2019: Molecular Reproduction and Development
Erin M Leonard, Min Zhang, Colin A Nurse
NEW FINDINGS: What is the central question of this study? The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O2 and CO2 /H+ homeostasis. Recent studies suggest that 5-HT, released from CB receptor cells, can stimulate adjacent glial-like type II cells, leading to an increase in intracellular Ca2+ (Δ[Ca2+ ]i ) and activation of ATP-permeable pannexin-1 (Panx-1) channels. The aim of this study was to elucidate the role of protein kinases in the 5-HT-[Ca2+ ]i -Panx-1 signalling pathway...
February 2019: Experimental Physiology
Hana Jin, Young Shin Ko, Hye Jung Kim
In the tumor microenvironment, extracellular nucleotides are released and accumulate, and can activate the P2Y2 receptor (P2Y2R), which regulates various responses in tumor cells, resulting in tumor progression and metastasis. Moreover, the inflammasome has recently been reported to be associated with tumor progression. However, the role of P2Y2R in inflammasome activation in breast cancer cells is not yet well defined. Therefore, in this study, we investigated the role of P2Y2R in inflammasome-mediated tumor progression in breast cancer using breast cancer cells and radiotherapy-resistant (RT‑R) breast cancer cells...
November 2018: International Journal of Oncology
Laura Rennert, Stefan Zschiedrich, Lukas Sandner, Björn Hartleben, Sanja Cicko, Cemil Korcan Ayata, Charlotte Meyer, Andreas Zech, Robert Zeiser, Tobias B Huber, Marco Idzko, Florian Grahammer
Endogenously released adenosine-5'-triphosphate (ATP) is a key regulator of physiological function and inflammatory responses in the kidney. Genetic or pharmacological inhibition of purinergic receptors has been linked to attenuation of inflammatory disorders and hence constitutes promising new avenues for halting and reverting inflammatory renal diseases. However, the involvement of purinergic receptors in glomerulonephritis (GN) has only been incompletely mapped. Here, we demonstrate that induction of GN in an experimental antibody-mediated GN model results in a significant increase of urinary ATP-levels and an upregulation of P2Y2R expression in resident kidney cells as well as infiltrating leukocytes pointing toward a possible role of the ATP/P2Y2R-axis in glomerular disease initiation...
2018: Frontiers in Immunology
Irena Svobodova, Anirban Bhattaracharya, Milorad Ivetic, Zdenka Bendova, Hana Zemkova
The circadian rhythms in physiological and behavioral functions are driven by a pacemaker located in the suprachiasmatic nucleus (SCN). The rhythms continue in constant darkness and depend on cell-cell communication between neurons and glia. The SCN astrocytes generate also a circadian rhythm in extracellular adenosine 5'-triphosphate (ATP) accumulation, but molecular mechanisms that regulate ATP release are poorly understood. Here, we tested the hypothesis that ATP is released via the plasma membrane purinergic P2X7 receptors (P2X7Rs) and P2Y receptors (P2YRs) which have been previously shown to be expressed in the SCN tissue at transcriptional level...
2018: Frontiers in Pharmacology
Shuo Li, Gaixiang Hao, Yaqi Xu, Nan Wang, Jiafang Li, Xuyun Geng, Jinsheng Sun
G-protein-coupled P2Y receptors activated by extracellular nucleotides play important roles under different physiological and pathophysiological conditions in mammals. To investigate the immunological relevance of P2Y receptors in fish, we identified and characterized the P2Y2 and P2Y12 receptors in Japanese flounder Paralichthys olivaceus. The P. olivaceus P2Y2 and P2Y12 receptors harbor seven transmembrane domains but share only 24% sequence identity. Real-time PCR analysis revealed the constitutive but unequal mRNA expression pattern of P2Y2 R and P2Y12 R in normal Japanese flounder tissues with the dominant expression of P2Y2 R in head kidney and blood and P2Y12 R in hepatopancreas...
April 2018: Fish & Shellfish Immunology
Laura de Diego García, Álvaro Sebastián-Serrano, Ivó H Hernández, Jesús Pintor, José J Lucas, Miguel Díaz-Hernández
The disturbances of cellular proteostasis caused by the alteration in the ubiquitin-proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuroinflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y2 R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process. With the use of mice expressing a UPS reporter [mice expressing the UPS reporter ubiquitinG76V -green fluorescent protein (UbGFP mice)], we found that LPS-induced acute neuroinflammation status causes a UPS impairment in astrocytes and microglial cells by a mechanism dependent on P2Y2 R...
June 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Maya Abe, Kanae Watanabe, Yoshiyuki Kuroda, Tetsuto Nakagawa, Hideyoshi Higashi
Many class C G-protein coupled receptors (GPCRs) function as homo- or heterodimers and several class A GPCRs have also been shown to form a homodimer. We expressed human P2Y2 receptor (P2Y2R) in cultured cells and compared SDS-PAGE patterns under reducing and non-reducing conditions. Under non-reducing conditions, approximately half of the P2Y2Rs were electrophoresed as a dimer. We then produced Cys to Ser mutants at four sites (Cys25, Cys106, Cys183 and Cys278) in the extracellular domains of P2Y2R and examined the effect on dimer formation and receptor activity...
June 1, 2018: Journal of Biochemistry
Geoffrey Burnstock, Kenneth A Jacobson, Fievos L Christofi
Purinergic receptors are implicated in the pathogenesis of gastrointestinal disorders and are being explored as potential therapeutic targets. Gut inflammation releases ATP that acts on neuronal, glial, epithelial and immune cells. Purinergic signalling in glia and neurons is implicated in enteric neuropathies. Inflammation activates glia to increase ATP release and alter purinergic signalling. ATP release causes neuron death and gut motor dysfunction in colitis via a P2X7-dependent neural-glial pathway and a glial purinergic-connexin-43 pathway...
December 2017: Current Opinion in Pharmacology
Nicholas Kindon, Andrew Davis, Iain Dougall, John Dixon, Timothy Johnson, Iain Walters, Steve Thom, Kenneth McKechnie, Premji Meghani, Michael J Stocks
The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2 R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2 R agonist UTP as the chemical starting point...
November 1, 2017: Bioorganic & Medicinal Chemistry Letters
Muhammad Rafehi, Alexander Neumann, Younis Baqi, Enas M Malik, Michael Wiese, Vigneshwaran Namasivayam, Christa E Müller
A homology model of the nucleotide-activated P2Y2 R was created based on the X-ray structures of the P2Y1 receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP...
October 26, 2017: Journal of Medicinal Chemistry
Farid G Khalafalla, Steven Greene, Hashim Khan, Kelli Ilves, Megan M Monsanto, Roberto Alvarez, Monica Chavarria, Jonathan Nguyen, Benjamin Norman, Walter P Dembitsky, Mark A Sussman
RATIONALE: Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged patients with HF with genetic predispositions and comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impair overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with proregenerative molecules ex vivo is crucial for improving the therapeutic outcome in patients with HF...
November 10, 2017: Circulation Research
Virginie Bondu, Chenyu Wu, Wenpeng Cao, Peter C Simons, Jennifer Gillette, Jieqing Zhu, Laurie Erb, X Frank Zhang, Tione Buranda
Pathogenic hantaviruses bind to the plexin-semaphorin-integrin (PSI) domain of inactive, β3 integrins. Previous studies have implicated a cognate cis interaction between the bent conformation β5 /β3 integrins and an arginine-glycine-aspartic acid (RGD) sequence in the first extracellular loop of P2Y2 R. With single-molecule atomic force microscopy, we show a specific interaction between an atomic force microscopy tip decorated with recombinant αIIb β3 integrins and (RGD)P2Y2 R expressed on cell membranes...
October 15, 2017: Molecular Biology of the Cell
Maria Ellegaard, Cansu Agca, Solveig Petersen, Ankita Agrawal, Lars Schack Kruse, Ning Wang, Alison Gartland, Jens-Erik Beck Jensen, Niklas Rye Jørgensen, Yuksel Agca
It is now widely recognized that purinergic signaling plays an important role in the regulation of bone remodeling. One receptor subtype, which has been suggested to be involved in this regulation, is the P2Y2 receptor (P2Y2R). In the present study, we investigated the effect of P2Y2R overexpression on bone status and bone cell function using a transgenic rat. Three-month-old female transgenic Sprague Dawley rats overexpressing P2Y2R (P2Y2R-Tg) showed higher bone strength of the femoral neck. Histomorphometry showed increase in resorptive surfaces and reduction in mineralizing surfaces...
December 2017: Purinergic Signalling
Isabel R Orriss, Dilek Guneri, Mark O R Hajjawi, Kristy Shaw, Jessal J Patel, Timothy R Arnett
Bone cells constitutively release ATP into the extracellular environment where it acts locally via P2 receptors to regulate bone cell function. Whilst P2Y2 receptor stimulation regulates bone mineralisation, the functional effects of this receptor in osteoclasts remain unknown. This investigation used the P2Y2 receptor knockout ( P2Y2 R- / - ) mouse model to investigate the role of this receptor in bone. MicroCT analysis of P2Y2 R -/- mice demonstrated age-related increases in trabecular bone volume (≤48%), number (≤30%) and thickness (≤17%)...
June 2017: Journal of Endocrinology
Sindhubarathi Murali, Min Zhang, Colin A Nurse
KEY POINTS: 5-HT is a neuromodulator released from carotid body (CB) chemoreceptor (type I) cells and facilitates the sensory discharge following chronic intermittent hypoxia (CIH). In the present study, we show that, in addition to type I cells, adjacent glial-like type II cells express functional, ketanserin-sensitive 5-HT2 receptors, and their stimulation increases cytoplasmic Ca2+ derived from intracellular stores. In type II cells, 5-HT activated a ketanserin-sensitive inward current (I5-HT ) that was similar to that (IUTP ) activated by the P2Y2R agonist, UTP...
July 1, 2017: Journal of Physiology
Tetsuto Nakagawa, Chihiro Takahashi, Hitomi Matsuzaki, Shohei Takeyama, Shinpei Sato, Ayaka Sato, Yoshiyuki Kuroda, Hideyoshi Higashi
P2Y2 receptor (P2Y2 R) is a G-protein-coupled receptor (GPCR) that couples with Gαq/11 and is stimulated by ATP and UTP. P2Y2 R is involved in pain, proinflammatory changes, and blood pressure control. Some GPCRs are localized in lipid rafts for interaction with other signaling molecules. In this study, we prepared N-glycan-deficient mutants by mutating the two consensus Asn residues for N-glycosylation to Gln to examine intracellular localization and association with lipid rafts. Western blotting of the wild type (WT) protein and mutants (N9Q, N13Q, N9Q/N13Q) in COS-7 cells showed that both Asn residues were glycosylated in the WT...
April 1, 2017: Biochemical and Biophysical Research Communications
Shaomin Qian, Jenna N Regan, Maxwell T Shelton, April Hoggatt, Khalid S Mohammad, Paul B Herring, Cheikh I Seye
BACKGROUND AND AIMS: Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y2 receptor (P2Y2 R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. METHODS: Apolipoprotein E, P2Y2 R double knockout mice (ApoE-/- P2Y2 R-/- ) were used to determine the effect of P2Y2 R deficiency on vascular calcification in vivo...
February 2017: Atherosclerosis
Xingjuan Chen, Shaomin Qian, April Hoggatt, Hongying Tang, Timothy A Hacker, Alexander G Obukhov, Paul B Herring, Cheikh I Seye
OBJECTIVE: Nucleotide P2Y2 receptor (P2Y2 R) contributes to vascular inflammation by increasing vascular cell adhesion molecule-1 expression in endothelial cells (EC), and global P2Y2 R deficiency prevents fatty streak formation in apolipoprotein E null (ApoE-/- ) mice. Because P2Y2 R is ubiquitously expressed in vascular cells, we investigated the contribution of endothelial P2Y2 R in the pathogenesis of atherosclerosis. APPROACH AND RESULTS: EC-specific P2Y2 R-deficient mice were generated by breeding VEcadherin5-Cre mice with the P2Y2 R floxed mice...
January 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Laura de Diego-García, Mercedes Ramírez-Escudero, Álvaro Sebastián-Serrano, Juan Ignacio Diaz-Hernández, Jesús Pintor, José J Lucas, Miguel Díaz-Hernández
The Ubiquitin-Proteasome System (UPS) is essential for the regulation of the cellular proteostasis. Indeed, it has been postulated that an UPS dysregulation is the common mechanism that underlies several neurological disorders. Considering that extracellular nucleotides, through their selective P2Y2 receptor (P2Y2 R), play a neuroprotective role in various neurological disorders that course with an UPS impairment, we wonder if this neuroprotective capacity resulted from their ability to modulate the UPS. Using a cellular model expressing two different UPS reporters, we found that the stimulation of P2Y2 R by its selective agonist Up4 U induced a significant reduction of UPS reporter levels...
January 2017: Biochimica et Biophysica Acta. Molecular Basis of Disease
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